Project Summary The development and formation of normal and abnormal vasculature is of critical importance to both normal biology and disease pathogenesis. Vascular homeostasis plays an important role in maintenance of normal vessel and organ function. Recent studies from our and other laboratories have established that ERK1/2 (extracellular receptor kinases 1 and 2) are critical to these processes. Yet there is a very limited understanding of what these kinases do and how this is accomplished. We propose to determine relative contributions of ERK1 vs. ERK2 to arterial fate specification and arteriogenesis, establish key steps in regulation of the ERK activity, discovery downstream signaling pathways, and decipher functional effects of ERK1 vs. ERK2 signaling. In preliminary studies we have observed abnormal arteriogenesis in mice missing the ERK1 isoform and abnormal angiogenesis in mice missing the ERK2 isoform. These data point to unexpected specificity of these kinases? activity that open a possibility of selectively targeting these two processes. The ability to do so would be of tremendous clinical significance.